1Neuroimaging Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA. bhahn@intra.nida.nih.gov

Abstract

Nicotine-induced attentional enhancement is of potential therapeutic value. To investigate the precise attentional function(s) affected and their neuronal mechanisms, the current functional magnetic resonance imaging (fMRI) study used an attention task in which subjects responded to stimuli of high (INT(high)) or low intensity presented randomly in one of four peripheral locations. Central cues of varying precision predicted the target location. In some trials, the cue was not followed by a target, allowing separate analysis of blood oxygenation level-dependent (BOLD) responses to cue. Minimally deprived smokers underwent fast event-related fMRI twice: once with a nicotine patch (21 mg) and once with a placebo patch. Matched nonsmokers were scanned twice without a patch. Behaviorally, nicotine reduced omission errors and reaction time (RT) of valid and invalid cue trials and intra-individual variability of RT and did so preferentially in trials with INT(high). The BOLD signal related to cue-only trials, regardless of cue precision, demonstrated nicotine-induced deactivation in anterior and posterior cingulate, angular gyrus, middle frontal gyrus, and cuneus. These regions overlapped with the so-called "default network," which activates during rest and deactivates with attention-demanding activities. Partial correlations controlling for nicotine plasma levels indicated associations of deactivation by nicotine in posterior cingulate and angular gyrus with performance improvements under INT(high). Performance and regional activity in the absence of nicotine never differed between smokers and nonsmokers, ruling out a simple reversal of a deprivation-induced state. These findings suggest that nicotine improved attentional performance by downregulating resting brain function in response to task-related cues. Together with the selectivity of effects for INT(high), this suggests a nicotine-induced potentiation of the alerting properties of external stimuli.

Onset of a central cue preceded target onset by a variable SOA. The target was presented for 500 ms in the continuing presence of the cue, which remained on display until 500 ms after target offset. Only screen background was then presented for an intertrial interval (ITI) that varied in length such that total trial duration was always 2700 ms. Cue-only trials differed only in that no target occurred. One, two, three or all four target locations could be cued at the same time, thus varying the predictability of the target.

The effects of nicotine on HR (beats per minute, bpm) 30, 60 and 120 min following nicotine patch application and after completion of the MR scan. Data are presented as averages ± SEM over 17 subjects.

Effects of nicotine on activity in valid target trials within regions identified by analysis of cue-only trials

Activity in valid target trials was averaged within regions of the brain identified by voxel-wise ANOVA of cue-only trials and compared between the nicotine and placebo session by paired t-tests (# P<0.05, ## P<0.01). Different from zero: * P<0.05, ** P<0.01, *** P<0.001, one sample t-test. Bars represent the average ± SEM (n=17). Abbreviations as in Fig. 4.

Correlations between effects of nicotine on default regions and on task performance

Partial correlations, controlling for nicotine plasma levels, between nicotine-induced deactivations of cue-related signal in posterior cingulate cortex (PCC), subparietal sulcus (SPS) and angular gyrus, and nicotine-induced reductions in the RT of validly (RTval) and invalidly cued trials (RTinval) and the standard deviation of RT in valid trials (RTvalstdev) with high-intensity targets. For RTval, correlations were determined separately for trials with one and four cued locations (1CUE, 4CUE), and for RTinval and RTvalstdev collapsed over cue conditions. Both axes represent difference (Δ) values, i.e. values in the placebo session subtracted from those in the nicotine session.